title: Steady-state plasma concentration of donepezil enantiomers and its stereoselective metabolism and transport in vitro.
abstract: The aim of the present study was to elucidate the differences in the plasma concentration of two enantiomers of donepezil in Chinese patients with Alzheimer's disease (AD) and investigate in vitro stereoselective metabolism and transport. Donepezil enantiomers were separated and determined by LC-MS/MS using D5-donepezil as an internal standard on a Sepax Chiralomix SB-5 column. In vitro stereoselective metabolism and transport of donepezil were investigated in human liver microsomes and MDCKII-MDR1 cell monolayer. Pre-dose (Css-min) plasma concentrations were determined in 52 patients. The mean plasma level of (R)-donepezil was 14.94 ng/ml and that of (S)-donepezil was 23.37 ng/ml. One patient's plasma concentration of (R)-donepezil was higher than (S)-donepezil and the ratio is 1.51. The mean plasma levels of (S)-donepezil were found to be higher than those of (R)-donepezil in 51 patients and the ratio of plasma (R)- to (S)-donepezil varies from 0.34 to 0.85. In the in vitro microsomal system, (R)-donepezil degraded faster than (S)-donepezil. V(max) of (R)-donepezil was significantly higher than (S)-donepezil. The P-gp inhibition experiment shown that the P(app) of the two enantiomers was higher than 200 and the efflux ratios were 1.11 and 0.99. The results of the P-gp inhibition identification experiment showed IC50 values of 35.5 and 20.4 μM, respectively, for the two enantiomers. The results indicate that donepezil exhibits stereoselective hepatic metabolism that may explain the differences in the steady-state plasma concentrations observed. Neither (R)- nor (S)-donepezil was a P-gp substance and the two enantiomers are highly permeable through the blood-brain barrier.
authors.affiliation: Department of Pharmacy, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai 200233, P. R. China.
authors.forename: Wan
authors.initials: W
authors.lastname: Lili
authors.forename: Guo
authors.initials: G
authors.lastname: Cheng
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhiyong
authors.forename: Yu
authors.initials: Y
authors.lastname: Qi
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.forename: Li
authors.initials: L
authors.lastname: Dan
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xueli
authors.forename: Zhong
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy; D002800:Cholinesterase Inhibitors / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D000077265:Donepezil; D004355:Drug Stability; D005260:Female; D006801:Humans; D007189:Indans / Q000097:blood* / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000737:chemistry; D010880:Piperidines / Q000097:blood* / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil
keywords: donepezil; enantiomers; metabolism; plasma concentration; stereoselective; transport